Phosphaplatins are pyrophosphate coordinated platinum(II) and platinum(IV) complexes containing inert amine ligands (R. J. Mishur, et al., Synthesis and X-ray crystallographic Characterization of Monomeric Platinum(II)- and Platinum(IV)-Pyrophosphato Complexes, Inorg. Chem., 2008, 47, 7972-7982). These compounds show excellent antitumor activities against a variety of human cancers as demonstrated by both in vitro (R. N. Bose, et al., Non-DNA Binding Platinum Anticancer Agents: Remarkable Cytotoxic Activities of Platinum-phosphato Complexes Towards Human Ovarian Cancer Cells, Proc. Natl. Acad. Sci., 2008, 105, 18314-18419) and in vivo experiments using Scid and Nude mice (S. Moghaddas, et al., Superior Efficacy of Phosphaplatins: Novel Non-DNA-Binding Platinum Drugs for Human Ovarian Cancer, FASEB J., 2010, 24:527; S. Moghaddas, et al., Phosphaplatins, Next Generation Platinum Antitumor Agents: A Paradigm Shift in Designing and Defining Molecular Targets, Inorg. Chim. Acta., DOI, 10.1016/j.ica.2012.05.040, ISSN 0020-1693). Moreover, these compounds show reduced toxicity compared to other platinum chemotherapeutics.
Current methods for synthesizing phosphoplatins, as described in published articles (R. J. Mishur, et al., Synthesis and X-ray crystallographic Characterization of Monomeric Platinum(II)- and Platinum(IV)-Pyrophosphato Complexes, Inorg. Chem., 2008, 47, 7972-7982) and in issued and pending patent applications (U.S. Pat. No. 7,700,649; U.S. Pat. No. 8,034,964; WO2011/053365), the contents of which are herein incorporated by reference in their entirety, require large reaction volumes to produce small quantities of products. These established methods are limited by the solubility of the starting platinum reactants. For example, to produce (trans-1,2-Cyclohexanediamine) (dihydrogen pyrophosphato) platinum(II) complex in 50 to 70 mg quantities, a starting volume of aqueous solution of 250 mL is required. Furthermore, to precipitate the same quantity of compound, the original volume needs to be reduced from 250 mL to 5 mL. Therefore, to scale up the synthesis to one kilogram of the compound, five thousand liters of starting volume is needed. Also, the cost for reducing such a large volume from 5000 L to 100 L to precipitate the product is significant. Secondly, the reported methodology does not recycle for use the un-reacted platinum starting reagent and excess pyrophosphate. Finally, the established large-volume synthesis requires a long reaction time, usually 12 to 24 hr for a batch of 50 to 70 mg materials. Therefore, there is a need in the art for a process that synthesizes large quantities of phosphaplatins for treating cancer patients and other applications where significant quantities of compounds will be required, and that optimally uses the reactants for maximum yield, and reduces reaction time.